ABSTRACT This is a shared equipment proposal to acquire a state-of-the-art histology wet lab system and microscopy system at the Seattle VA Puget Sound Health Care System (VAPSHCS), under the auspices of the ORD Shared Equipment Program. The proposed system to be acquired through this program will comprise an integrated wet lab histology system [tissue processor (Leica ASP300S), embedding station (Arcadia H/C), microtome (Leica CM3050S), automated staining station (Leica Autostainer XL)], and fully motorized upright microscope equipped for brightfield and epifluorescence microscopy and capable of generating high resolution large area (i.e. whole section) scans (Nikon NiE microscope). These instruments form a comprehensive tissue to image/data system that will be housed within the VAPSHCS?s Cellular and Molecular Imaging Core. The proposed equipment purchases will upgrade existing outmoded/non-functional technology that is critical to the ongoing research of Cellular and Molecular Imaging Core users. Specifically the existing tissue processor, embedding station and microtome that serve the Core user base are all at least 10 years old and all are requiring frequent repairs of increasing scope and thus cost. New equipment will clearly reduce these expenditures allowing resources to be more effectively used to support the ongoing research program at VAPSHCS. The proposed instrument system is centered on the preparation of samples for measurement of cellular morphology and changes in amount and localization of molecules therein that occur with disease progression. Importantly, it is widely applicable to our diverse community of researchers which includes, but is not limited to, scientists doing research in the areas of diabetes and metabolism, vascular biology, and neuroscience including Alzheimer?s disease and traumatic brain injury. Twelve investigators use the currently available, outdated instruments in the core and will benefit greatly from these upgraded versions. All users have enthusiastically indicated that they will use the upgraded instruments. Of these, eight have VA-funded research programs (are major users, accounting for ~75% of instrument time; approx. 28 hours per week) while four minor users have research programs funded by national peer-reviewed agencies (e.g. NIH) and will use the new instruments for 10 hours per week (the remaining 2 hours is required for instrument maintenance and quality control). We present in this proposal a comprehensive plan for the sharing, administration, and care of the instruments, and how different VA investigators will take advantage of this advanced technology. In the Research Plan section of this proposal, we present details as to how each investigator will use these shared instruments and how they will benefit their research program. Herein are excerpts to summarize some of these different uses: ? Delineating activation of intracellular stress signaling pathways and triggering of apoptosis, which mediate amyloid-induced -cell loss as it relates to type 2 diabetes pathogenesis. ? Identification of specific brain cells (e.g. neurons and microglia) in postmortem human samples and those from animal models of blast trauma, and Alzheimer?s disease. ? Determine the extent of and mechanisms underlying loss of islet sympathetic nerves in type 1 diabetes. ? Measuring gene expression changes in response to drug treatment; quantitation of neurodegeneration- related pathology. ? Analyzing the effect of mutations in the STAT-1 protein on the numbers and types of cells present in atherosclerotic vessels. In summary, this new instrument package will provide a state-of-the-art scientific platform to support many investigators based at VAPSHCS in Seattle. The instrument will be located and managed by the established Cellular and Molecular Imaging Core, which already includes well-developed administrative and technical infrastructure for the management, scheduling, and support of the Core?s assets.